The androgen receptor is a primary target of prostate cancer treatment and prevention. For metastatic prostate cancer(androgen responsive), androgen deprivation therapy (ADT) has been the standard mode of treatment. The tumors initially respond with the inhibition of growth, but most tumors invariably relapse leading to a lethal castration resistant prostate cancer(CRPC), indicating a shift in tumor responsiveness. The proliferating primary tumor recruits a variety of stromal cells in its surrounding microenvironment, which facilitates its growth and ultimately invasion and metastasis to distant organs. The myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg) are important components of the immune suppressive network of the tumor microenvironment (TMEN). MDSCs play a pivotal role in suppression of both innate and adaptive immunity and its presence is documented both in preclinical model and cancer patients. The role of MDSCs in prostate cancer CRPC and metastasis is poorly understood. The unanswered questions include how MDSCs facilitate the tumor cells to evade the host immune surveillance, and what pathway regulates MDSC recruitment, accumulation, proliferation and differentiation in prostate cancer. Using the PB-Cre4/PTENL/L/SMAD4L/L and PB-Cre4/PTENL/L/Trp53L/L/ SMAD4L/L mouse model this project will first characterize MDSC population in both primary tumors as well as castration resistant tumors. Then we will identify novel prostate cancer specific MDSC markers using genomic and proteomic technology and finally, we will propose pre-clinical model to validate our newly discovered targets to deplete MDSCs to prevent/treat CRPC.